Dihydroisoquinolines are important synthetic intermediates to many morphinan compounds including burprenorphine, codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone and naltrexone are opiate receptor antagonists; and are used for reversal of narcotic/respiratory depression due to opiate receptor agonists.
Rice (U.S. Pat. No. 4,521,601) discloses the reaction of 3-methoxy phenethylamine with 2-hydroxy-3-methoxyphenylacetic acid at 200° C. under argon. Generally, for a viable large scale production of the resulting amide compound, 200° C. is too high. For example, most large scale reaction vessels cannot routinely reach or sustain temperatures above 140° C.; thus, in order for large scale production of the morphinans, a special reactor or reactor heating unit is needed.
The Bischler-Napieralski cyclization generally converts an appropriately substituted amide to a 3,4-dihydroisoquinoline. Typically, when a free phenol group is present in the acid, and thus, also present in the amide, the cyclization requires more POCl3, longer reaction times, and higher reaction temperatures, because the POCl3 is known to react directly with the hydroxyl group of the phenol to produce phosphoryl halides. Reaction side products of poly-phosphates and incomplete hydrolysis of the phosphate groups usually result in decreased yields and difficult purification of the desired 3,4-dihydroisoquinoline products. Various protecting groups, particularly ether protecting groups, have been used to reduce the above problems in this cyclization step. However, use of these derivatives requires an additional synthetic step using harsh reagents and conditions to produce the free phenol. Thus, a need still exists for a synthetic method that requires reduced amounts of phosphorus oxychloride, lowered reaction times, reduced temperatures, simplified work-up and isolation, and does not require additional harsh synthetic steps to remove a phenol protecting group.